Abstract
CYP3A1 gene (P450/6betaB) encodes testosterone 6beta-hydroxylase (EC 1.14.14.1) in rats. The promoter region of CYP3A1 gene contains three binding sites for nuclear factors: 6betaB-A (-105 to -86), 6betaB-B (-139 to -118), and 6betaB-C (-164 to -145). The 6betaB-A site shows a high degree of similarity to a consensus sequence of the binding site of hepatocyte nuclear factor 4 (HNF-4) and also to the 6betaA-A site on the rat CYP3A2 gene promoter region. Our previous study suggested an involvement of the 6betaA-A site in the basal transactivation of CYP3A2 gene using HepG2 cells. In the present study, transactivation through the 6betaB-A and 6betaA-A sites of CYP3A1 and CYP3A2 genes has directly been shown by coexpression of HNF-4 and CYP3A1 or CYP3A2 promoter-reporter fused genes. Similar experiments further showed that nuclear factor binding at the 6betaB-B site hampered HNF-4-mediated transactivation of CYP3A1 gene. Recombinant apolipoprotein AI regulatory protein I (ARP-1) and v-ErbA-related protein 3 (EAR-3) are shown to suppress HNF-4-mediated activation at the 6betaB-B site without competition of HNF-4.
Copyright 1999 Academic Press.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Aryl Hydrocarbon Hydroxylases*
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Base Sequence
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Binding, Competitive / genetics
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COS Cells
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COUP Transcription Factor I
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COUP Transcription Factor II
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COUP Transcription Factors
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Cytochrome P-450 CYP3A
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Cytochrome P-450 Enzyme System / genetics*
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology*
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Hepatocyte Nuclear Factor 4
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Mixed Function Oxygenases / genetics*
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Molecular Sequence Data
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Phosphoproteins / physiology*
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Rats
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Receptors, Steroid / metabolism
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Repressor Proteins / physiology
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Sequence Deletion
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Steroid Hydroxylases / genetics
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Transcription Factors / metabolism
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Transcription Factors / physiology*
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Transcriptional Activation*
Substances
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COUP Transcription Factor I
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COUP Transcription Factor II
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COUP Transcription Factors
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DNA-Binding Proteins
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Hepatocyte Nuclear Factor 4
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Nr2f1 protein, rat
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Nr2f2 protein, rat
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Phosphoproteins
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Receptors, Steroid
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Repressor Proteins
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Transcription Factors
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Cytochrome P-450 Enzyme System
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Mixed Function Oxygenases
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Steroid Hydroxylases
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Aryl Hydrocarbon Hydroxylases
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CYP3A protein, human
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Cyp3a23-3a1 protein, rat
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Cytochrome P-450 CYP3A
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steroid hormone 6-beta-hydroxylase